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Daily administration of the GIP‐R antagonist (Pro 3 )GIP in streptozotocin‐induced diabetes suggests that insulin‐dependent mechanisms are critical to anti–obesity‐diabetes actions of (Pro 3 )GIP
Author(s) -
McClean P. L.,
Gault V. A.,
Irwin N.,
McCluskey J. T.,
Flatt P. R.
Publication year - 2008
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2007.00712.x
Subject(s) - medicine , endocrinology , islet , streptozotocin , insulin , diabetes mellitus , antagonism , insulin resistance , type 2 diabetes , obesity , antagonist , receptor
Aim: Glucose‐dependent insulinotropic polypeptide‐receptor (GIP‐R) antagonism using (Pro 3 )GIP improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure and function in a commonly used model of obesity‐diabetes, namely ob/ob mice. The effect of GIP‐R antagonism in a streptozotocin (STZ)‐induced model of insulin deficiency has not been evaluated. The present study has investigated the effects of daily administration of (Pro 3 )GIP to STZ‐treated mice. Methods: Swiss TO mice received once‐daily injection of (Pro 3 )GIP (25 nmol/kg body weight) or saline 4 days prior to and 16 days after injection of STZ, and effects on metabolic parameters and islet architecture were assessed. Results: (Pro 3 )GIP treatment had no significant effect on hyperphagia or body weight loss. However, hyperglycaemia and glycated haemoglobin were worsened, glucose tolerance further decreased and insulin sensitivity was impaired by (Pro 3 )GIP. These effects were observed on an STZ‐induced background characterized by severe reductions of circulating insulin, beta‐cell mass and pancreatic insulin stores. Conclusions: These data indicate that the beneficial actions of the GIP‐R antagonist, (Pro 3 )GIP, in obesity‐diabetes appear to be largely mediated through insulin‐dependent mechanisms that merit further investigation.